The work in progress is an ongoing study concerning the interaction of diphtheria toxin with diphtheria susceptible and resistant mammalian cells in culture. The ultimate objectives are two fold. 1) To determine the essential differences between the susceptible and resistant cells types. It is now apparent that the crucial differences reside at the level of the plasma membrane. Resistant cells either lack specific toxin receptors or appropriate enzymes to "activate toxin". To date we have no evidence for specific toxin receptors (reagents which bind specifically with SH groups, glycoproteins and a number of enzymes do not alter kinetics of toxicity significantly) although we have found that toxicity may be expressed in a non-ionic environment suggesting that electrostatic forces are not required for initial toxin-cell adsorption to occur. 2) To determine how toxin, once adsorbed to the plasma membrane reaches the cytosol where it interacts with cytoplasmic components and results in shut-down of protein-synthesis. We have evidence that both suceptible and resistant cells internalize toxin by pinocytosis but that in most cases toxicity is not expressed. Under some circumstances (i.e., piggy back phagocytosis) toxicity in membrane bound vesicles may be expressed. We postulate that an alternative mechanism of toxin internalization occurs whereby toxin traverses the membrane without vesicle formation. Another facet of our investigation is to study modifiers of toxicity. Major attention has been given to ammonium chloride, a compound which presents completely any expression of toxicity by diphtheriat toxin. Other substances, such as arsenicals which are partially protective are also under investigation.